Targeting SHP2 Cryptic Allosteric Sites for Effective Cancer Therapy.

ABSTRACT: SHP2, a pivotal component downstream of both receptor and non-receptor tyrosine kinases, has been underscored in the progression of various human cancers and neurodevelopmental disorders. Allosteric inhibitors have been proposed to regulate its autoinhibition. However, oncogenic mutations, such as E76K, convert SHP2 into its open state, wherein the catalytic cleft becomes fully exposed to its ligands. This study elucidates the dynamic properties of SHP2 structures across different states, with a focus on the effects of oncogenic mutation on two known binding sites of allosteric inhibitors. Through extensive modeling and simulations, we further identified an alternative allosteric binding pocket in solution structures. Additional analysis provides insights into the dynamics and stability of

SUBMITTER: Rehman AU 

PROVIDER: S-EPMC11172685 | biostudies-literature | 2024 Jun

REPOSITORIES: biostudies-literature